Abstract
Idiopathic multicentric Castleman disease (iMCD) is subclassified into iMCD- thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly (TAFRO), and iMCD-not otherwise specified (NOS) according to the Castleman Disease Collaborative Network (CDCN) consensus criteria. With a deeper understanding of iMCD, a group of patients with iMCD-NOS characterised by polyclonal hypergammaglobulinaemia, plasmacytic/mixed-type lymph node histopathology, and elevated platelet counts has attracted attention. This group of patients has been previously described as having idiopathic plasmacytic lymphadenopathy (IPL). Whether these patients should be excluded from the current classification system lacks sufficient evidence. This retrospective analysis of 228 patients with iMCD-NOS identified 103 (45.2%) patients with iMCD-IPL. The clinical features and outcomes of patients with iMCD-IPL and iMCD-NOS without IPL were compared. Patients with iMCD-IPL showed a significantly higher inflammatory state but longer overall survival. No significant difference in overall survival was observed between severe and non-severe patients in the iMCD-IPL group according to the CDCN severity classification. Compared with lymphoma-like treatments, multiple myeloma-like and IL-6 blocking treatment approaches in the iMCD-IPL group resulted in significantly higher response rates and longer time to the next treatment. These findings highlight the particularities of iMCD-IPL and suggest that it should be considered a new subtype of iMCD-NOS.
Keywords: idiopathic multicentric Castleman disease, idiopathic plasmacytic lymphadenopathy, polyclonal hypergammaglobulinaemia, thrombocytosis, plasmacytosis
Introduction
Idiopathic multicentric Castleman disease (iMCD) describes a group of rare and distinct lymphoproliferative disorders characterised by multicentric lymphadenopathy, systemic inflammatory symptoms, and varying degrees of organ dysfunction related to a cytokine storm (1). According to the Castleman Disease Collaborative Network (CDCN) consensus criteria, iMCD can be further classified into iMCD-thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) and iMCD-not otherwise specified (NOS) (2). iMCD-TAFRO is an established subgroup with similar clinical features, rapid progression, and often fatal results (3). In contrast, iMCD-NOS comprises a diverse collection of diseases with widely varying clinical manifestations, therapeutic responses, and prognoses (4). Recently, some patients with iMCD-NOS have been noted to present with distinct clinical manifestations and thus may be further ‘specified’ (5). These patients present with elevated immunoglobulin G (IgG) levels, plasmacytic or mixed-type lymph node histopathology, and thrombocytosis, which were previously described as iMCD-idiopathic plasmocytic lymphadenopathy (IPL) (6).
IPL was initially proposed in 1980 by Mori et al. and is characterised by systemic nodal plasmacytosis associated with severe polyclonal hyperimmunoglobulinaemia (6). The term MCD was established after Frizzera et al.’s landmark report in 1983 (7). IPL was considered identical to MCD (8) until the associations between MCD and human herpesvirus-8 (HHV-8; also known as Kaposi sarcoma-associated herpesvirus) and human immunodeficiency virus were noted. By 2008, Kojima et al. removed the HHV-8-associated MCD from the previous IPL framework (11). With the subsequent recognition of iMCD and TAFRO syndrome, IPL is currently considered a non-TAFRO subgroup of iMCD (2). In summary, with the understanding of CD, the position of the IPL in the entire CD spectrum has been constantly updated and revised.
In 2022, Nishikori et al. (9) analysed the clinical features of 42 patients with iMCD-NOS with and without IPL and determined that iMCD-IPL might form an independent subtype of iMCD. However, the sample size was small, and survival information was not compared between the two groups. Therefore, it remains necessary to delineate the clinical characteristics, treatment response, and long-term outcomes of this subgroup of patients to further understand iMCD-IPL and provide evidence for updating the current nosological framework. This retrospective study aimed to evaluate the clinical and prognostic characteristics of patients with iMCD-IPL, a subgroup that was previously classified as ‘iMCD-NOS’ (2), to compare them with other iMCD-NOS patients without IPL (iMCD-NOS w/o IPL). We aimed to determine whether iMCD-IPL could be considered a unique subtype independent of iMCD-NOS.
Materials and methods
Patients
This retrospective, single-centre study was approved by the Medical Ethics Committee of Peking Union Medical College Hospital (PUMCH). Patients diagnosed with iMCD-NOS from January 2000 to May 2023 at PUMCH were consecutively included (2).
The diagnostic criteria for iMCD-NOS were as follows: patients 1) with histopathological lymph node features consistent with Castleman disease spectrum, 2) with multiple lymph node region involvement (enlarged lymph nodes ≥1 cm in short-axis diameter in ≥2 lymph node stations), and 3) meeting at least two of the 11 minor criteria proposed by the CDCN (2) and not meeting 1) any of the exclusion criteria (infection-related disorders, autoimmune/autoinflammatory diseases, and malignant/lymphoproliferative disorders that mimic iMCD) proposed by the CDCN (2) or 2) iMCD-TAFRO criteria (10). The patients were further classified as having iMCD-IPL or iMCD-NOS w/o IPL. Three sets of diagnostic criteria (Mori et al. in 1980 (6), Kojima et al. in 2008 (11), and Zhang et al. in 2023 (5); Supplementary Table S1) are currently used to diagnose iMCD-IPL, with slight differences. In this study, iMCD-IPL was defined as described by Zhang et al. (5): (1) eligibility for the diagnostic criteria of iMCD-NOS (2), (2) elevated serum immunoglobulin G (IgG) level (>17.4 g/L), (3) plasmacytic or mixed pathological subtypes (2), and (4) elevated platelet count (>350×109/L). Patients with iMCD-NOS who did not meet these criteria were defined as having iMCD-NOS w/o IPL.
According to CDCN treatment consensus, patients were further classified as having severe or non-severe disease: severe iMCD should have at least two of the five following criteria: (1) Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) score ≥2 points, (2) stage IV renal dysfunction, (3) anasarca, (4) haemoglobin level of ≤80 g/L, and (5) pulmonary involvement/interstitial pneumonitis with dyspnoea (10).
Treatments and outcomes
Treatment options were classified as lymphoma-like treatments and multiple myeloma-like and IL-6 blocking treatments. Lymphoma-like treatment regimens included rituximab-containing regimens; cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like regimens; and etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin regimens. Multiple myeloma-like and IL-6 blocking treatment regimens included thalidomide-based regimens (thalidomide-cyclophosphamide-prednisone/thalidomide-cyclophosphamide-dexamethasone/thalidomide-glucocorticoids), bortezomib-based regimens (bortezomib-cyclophosphamide-dexamethasone/bortezomib-dexamethasone), glucocorticoid monotherapy, cyclophosphamide plus glucocorticoids, lenalidomide-based regimens (lenalidomide-dexamethasone), and interleukin (IL)-6 targeted therapy (siltuximab, tocilizumab, and novel IL-6 receptor monoclonal antibody).
The optimal response to first-line treatment in patients with iMCD-NOS was evaluated based on the CDCN response criteria (10). Complete remission (CR) was defined as the normalisation of laboratory test results and inflammation-related symptoms, along with a complete lymph node response. Partial remission (PR) was defined as improvement in all four symptom categories, >50% improvement in laboratory results, and >50% reduction in mass. Progressive disease (PD) was defined as >25% deterioration in laboratory test results, aggravation of any of the four inflammation-related symptoms, or >25% increase or recurrence of enlarged lymph nodes. Stable disease (SD) was defined as no PR, CR, or PD. The response state was defined as PR or CR, and SD or PD was defined as an inadequate response state.
Follow-up (until 30 June 2023) information was obtained from outpatient clinics, phone contacts, and records of visits in hospital databases. Overall survival (OS) was defined as the time interval between diagnosis and either death or last follow-up (in months). In the time-to-next-treatment (TTNT) analysis, TTNT was defined as the time from the initiation of the index regimen to the commencement of the subsequent line of therapy or death, whichever occurred earlier, or until the last follow-up.
Statistical analyses
Statistical analyses were performed using RStudio (version 4.2.0 ©2009–2022 RStudio, PBC RStudio). The baseline characteristics of patients with iMCD-NOS were assessed. The characteristics between iMCD-IPL and iMCD-NOS w/o IPL were compared using the Mann–Whitney U tests for continuous variables and Chi-square or Fisher’s exact tests for categorical variables. The time-to-event OS and TTNT endpoints were described using the Kaplan–Meier plots, and survival functions were compared using the log-rank test. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using a Cox proportional hazards model. Statistical significance was defined as two-tailed P-values of <0.05 for all analyses.
Results
Baseline characteristics
In total, 228 patients with iMCD-NOS were included in this study. One hundred and three patients (45.2%) were identified as having iMCD-IPL, comprising 54 males (52.4%), with a median age of 37 (range, 14–68) years at the time of diagnosis. The remaining 125 (54.8%) patients who did not meet the inclusion criteria for iMCD-IPL formed the iMCD-NOS w/o IPL group. The age of patients with iMCD-IPL was lower than that of patients with iMCD-NOS w/o IPL (37 vs. 46 years, P<0.001), whereas sex distribution was similar between groups (Table 1).
Table 1.
Demographic and clinical characteristics of patients with iMCD-NOS
| Normal range | All patients (n=228) | iMCD-IPL (n=103) | iMCD-NOS w/o IPL (n=125) | P-value | |
|---|---|---|---|---|---|
|
| |||||
| Age at diagnosis, years, median (range) | 41 (14–75) | 37 (14–68) | 46 (15–75) | <0.001 | |
| Sex, male, n (%) | 133 (58.3) | 54 (52.4) | 79 (63.2) | 0.101 | |
| Lymph node involvement, both sides of the diaphragm, n (%) | 172 (75.4) | 78 (75.7) | 94 (75.2) | 0.927 | |
| Histopathology, n (%) | <0.001 | ||||
| Hyaline vascular | 29 (12.7) | — | 29 (23.2) | ||
| Plasmacytic | 174 (76.3) | 93 (90.3) | 81 (64.8) | ||
| Mixed | 25 (11.0) | 10 (9.7) | 15 (12.0) | ||
| Clinical manifestations, n (%) | |||||
| Fever | 109 (47.8) | 52 (50.5) | 57 (46.3) | 0.535 | |
| Fatigue | 170 (74.6) | 75 (72.8) | 95 (77.2) | 0.443 | |
| Anorexia | 93 (40.8) | 36 (35.0) | 57 (47.1) | 0.066 | |
| Weight loss | 121 (53.1) | 59 (57.3) | 62 (52.1) | 0.439 | |
| Anasarca* | 43 (18.9) | 16 (15.5) | 27 (21.8) | 0.244 | |
| Hepatosplenomegaly | 99 (43.4) | 44 (42.7) | 55 (44.0) | 0.846 | |
| Pulmonary involvement | 112 (49.1) | 52 (50.5) | 60 (55.0) | 0.506 | |
| ECOG-PS ≥2, n (%) | 50 (21.9) | 17 (16.5) | 33 (26.4) | 0.072 | |
| Severity of iMCD, n (%) | 77 (33.8) | 32 (31.1) | 45 (36.0) | 0.433 | |
| Laboratory findings, median (IQR) | |||||
| Haemoglobin, g/L | Male, 120–160; female, 110–150 | 100.00 (83.00–117.00) | 91.00 (78.00–107.00) | 109.00 (87.50–124.00) | <0.001 |
| PLT, ×109/L | 100–350 | 358.00 (241.00–463.00) | 463.00 (404.00–580.00) | 251.50 (167.25–321.75) | <0.001 |
| Albumin, g/L | 35–52 | 31.00 (26.25–35.83) | 29.00 (25.00–33.00) | 33.00 (29.00–39.00) | <0.001 |
| ALP, U/L | 45–125 | 97.00 (72.00–159.00) | 120.50 (78.25–197.75) | 90.00 (68.00–126.00) | 0.001 |
| γ-globulin, g/L | 9.1–24.0 | 39.27 (23.81–56.09) | 51.40 (37.03–63.57) | 29.53 (17.94–44.48) | <0.001 |
| IgG, g/L | 7.00–17.00 | 32.29 (19.21–46.58) | 42.73 (29.68–54.95) | 23.77 (14.29–36.55) | <0.001 |
| Serum creatinine, μmol/L | Male, 59–104; female, 45–84 | 65.50 (53.00–79.70) | 60.00 (51.50–74.00) | 71.00 (57.00–89.00) | <0.001 |
| eGFR<60 mL/min/1.73 m2, n (%) | 25 (11.0) | 4 (4.0) | 21 (17.4) | 0.002 | |
| CRP, mg/L | 0–8 | 85.32 (28.69–147.87) | 129.64 (74.05–185.64) | 42.35 (15.61–111.04) | <0.001 |
| ESR, mm/h | 0–15 | 99.00 (76.00–114.00) | 107.00 (95.75–118.25) | 83.00 (44.00–103.00) | <0.001 |
| IL-6, pg/mL | <5.9 | 24.70 (11.08–57.25) | 40.60 (19.58–85.10) | 13.50 (6.63–35.50) | <0.001 |
Anasarca indicates pleural effusion, ascites, and/or generalised oedema.
Abbreviations: ECOG-PS, Eastern Cooperative Oncology Group Performance Status; PLT, platelet; ALP, alkaline phosphatase; IgG, immunoglobulin G; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; IL-6, interleukin-6; IQR, interquartile range
Of all patients with iMCD-IPL, 92 (90.3%) had the plasmacytic histopathological subtype and 10 (9.7%) had the mixed histopathological subtype. Seventy-eight (75.7%) patients had both supra- and infradiaphragmatic involvement. At presentation, 17 (16.5%) patients with iMCD-IPL had an ECOG-PS score of ≥2 points. The clinical manifestations showed no significant differences between the groups. Although observed in 16 (15.5%) patients with iMCD-IPL and 27 (21.8%) with iMCD-NOS without IPL, anasarca rates showed no difference between the two groups.
Compared with iMCD-NOS w/o IPL, patients with iMCD-IPL exhibited significantly higher platelet counts (median, 463 vs. 252; P<0.001) and hypergammaglobulinaemia levels (median, 42.73 vs. 23.77 for IgG and 51.40 vs. 29.53 for γ-globulin; both P<0.001). Although anaemia and hypoalbuminaemia were present in both groups, the iMCD-IPL group showed significantly lower haemoglobin (median, 91 vs. 109, P<0.001) and serum albumin (median, 29 vs. 33; P<0.001) levels than the iMCD-NOS w/o IPL group. C-reactive protein (CRP) level (median, 129.64 vs. 42.35; P<0.001), erythrocyte sedimentation rate (median, 107 vs. 83; P<0.001), and serum IL-6 level (median, 40.6 vs. 13.5; P<0.001) in patients with iMCD-IPL were significantly higher than those in patients with iMCD-NOS w/o IPL. However, impaired renal function was less common in patients with iMCD-IPL than in those with iMCD-NOS w/o IPL (estimated glomerular infiltration rate [eGFR]<60, 4% vs. 17.4%, P<0.001), and no patients with eGFR <30 were found in either group.
Among these patients with iMCD-IPL, all met the Zhang et al. definition for iMCD-IPL. However, 30 (29%) patients did not meet the Kojima et al. definition for not meeting their polyclonal hypergammaglobulinaemia criteria as γ-globin >4.0 g/dL or serum IgG level >3500 mg/dL (Supplementary Table S2).
Treatments and outcomes
Of the 103 patients with iMCD-IPL and 125 patients with iMCD-NOS w/o IPL, 101 and 115 received at least one treatment, of whom 98 and 99 had available response assessment data, respectively. For patients with iMCD-IPL, 85 (86.7%) received a multiple myeloma-like and IL-6 blocking treatment strategy and 13 (13.3%) received a lymphoma-like treatment strategy as their first-line treatment option. Significantly higher remission rates (80% vs. 31%, P<0.001) and longer TTNT (36.37 vs. 4.53, P=0.013) were observed in patients who received a multiple myeloma-like and IL-6 blocking treatment strategy (Table 2 and Figure 1). For patients with iMCD-NOS w/o IPL, the remission rate (P=0.278) and TTNT (P=0.278) showed no differences between the two treatment options.
Table 2.
First-line treatment options and outcomes in patients with iMCD-NOS
| Subtype | Treatment option | Treatment remission (%) | P-value | Median TTNT (m) | P-value |
|---|---|---|---|---|---|
|
| |||||
| iMCD-IPL (n=98) | Multiple myeloma-like and IL-6 blocking treatments (n=85) | 68/85 (80%) | <0.001 | 36.37 | <0.001 |
| Lymphoma-like treatments (n=13) | 4/13 (31%) | 4.53 | |||
| iMCD-NOS w/o IPL (n=99) | Multiple myeloma-like and IL-6 blocking treatments (n=75) | 51/75 (68%) | 0.794 | 63.13 | 0.278 |
| Lymphoma-like treatments (n=24) | 17/24 (71%) | 29.93 | |||
Abbreviation: TTNT (m), time to next treatment (months)
Figure 1.
TTNT between treatment options in patients with iMCD-NOS
Abbreviations: TTNT, time to next treatment
No significant differences in the first-line treatment choice (P=0.073) and response rate (P=0.459) were found between the two groups (Table 3). In both groups, thalidomide was the most commonly used first-line regimen (50% and 44%, iMCD-IPL and iMCD-NOS w/o IPL, respectively), followed by the bortezomib-based regimen (20% and 19%, respectively) and the CHOP regimen (9% and 21%, respectively). Siltuximab (6% and 1%) and tocilizumab (5% and 2%) as first-line treatments were rare because siltuximab was not available on the Chinese market until 2022 and tocilizumab was expensive and not approved for iMCD in China.
Table 3.
Disease management and optimal responses in patients with iMCD-NOS
| iMCD-IPL (n=101) | iMCD-NOS w/o IPL (n=115) | P | |
|---|---|---|---|
|
| |||
| First-line treatment | 0.073 | ||
| Thalidomide-based | 50/101 (50%) | 51/115 (44%) | |
| Bortezomib-based | 20/101 (20%) | 22/115 (19%) | |
| Tocilizumab | 5/101 (5%) | 2/115 (2%) | |
| Siltuximab | 6/101 (6%) | 1/115 (1%) | |
| Rituximab-based | 5/101 (5%) | 7/115 (6%) | |
| CHOP | 9/101 (9%) | 24/115 (21%) | |
| Remission after first-line treatment | 72/98 (73%) | 68/99 (69%) | 0.459 |
| Ever response to thalidomide | 0.043 | ||
| Remission | 50/64 (78%) | 31/51 (61%) | |
| Failure | 14/64 (22%) | 20/51 (39%) | |
| Ever response to bortezomib | 0.908 | ||
| Remission | 35/43 (81%) | 37/46 (80%) | |
| Failure | 8/43 (19%) | 9/46 (20%) | |
| Ever response to rituximab | 0.397 | ||
| Remission | 5/10 (50%) | 11/15 (73%) | |
| Failure | 5/10 (50%) | 4/15 (27%) | |
| Thalidomide use in | 0.006 | ||
| First-line | 50/64 (78%) | 49/51 (96%) | |
| Later-line | 14/64 (22%) | 2/51 (4%) | |
| Bortezomib use in | 0.621 | ||
| First-line | 20/43 (47%) | 19/46 (41%) | |
| Later-line | 23/43 (53%) | 27/46 (59%) | |
| Rituximab use in | 0.697 | ||
| First-line | 5/10 (50%) | 6/15 (40%) | |
| Later-line | 5/10 (50%) | 9/15 (60%) | |
Abbreviations: CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone
Significant P values are in bold.
When all treatment lines were considered, thalidomide remained the most commonly used treatment regimen for patients with iMCD-NOS, either iMCD-IPL or iMCD-NOS w/o IPL. Although thalidomide-based regimen was more frequently observed in later-line treatment in the iMCD-IPL group (22% vs. 4%, P=0.006), the response rate to thalidomide remained significantly higher than that in the iMCD-NOS w/o IPL group (78% vs. 61%, P=0.043). Bortezomib was administered to 43 patients with iMCD-IPL, of whom 35 (81%) achieved remission. Ten patients with iMCD-IPL received rituximab, of whom five (50%) responded. No significant differences in response to bortezomib or rituximab were found between the iMCD-IPL and iMCD-NOS w/o IPL groups.
Survival analyses
The median follow-up time of the 228 patients with iMCD-NOS was 56.10 months (range, 2–274). During follow-up, two (1.9%) patients with iMCD-IPL and 19 (15.2%) patients with iMCD-NOS w/o IPL died. Significant differences in survival were observed between groups, with patients with iMCD-NOS w/o IPL tending to have a poorer OS than those with iMCD-IPL (P=0.001; HR=7.526, 95% CI, 1.750–32.267; Figure 2). The median survival was not reached in either the iMCD-IPL or iMCD-NOS w/o IPL group, and the estimated 5-year OS rates were 97.0% and 85.5%, respectively.
Figure 2.
Overall survival plots in 228 patients with iMCD-NOS
According to the CDCN criteria, 32 (31.1%) patients with iMCD-IPL and 45 (36%) patients with iMCD-NOS w/o IPL were classified as having severe iMCD at baseline. Significant differences in survival rates between patients of different severity groups were observed in the iMCD-NOS w/o IPL group, with 12 ‘severe’ patients dying and seven ‘non-severe’ patients dying during the follow-up (P=0.018; HR=2.918; 95% CI, 1.148–7.418). However, among patients with iMCD-IPL, deaths occurred in one severe case and one non-severe case during the follow-up, with no significant difference in OS between severity classification (P=0.661; HR=1.843; 95% CI, 0.115–29.485) (Figure 3).
Figure 3.
Overall survival plots according to CDCN severity classification
Abbreviation: CDCN, Castleman Disease Collaborative Network
Discussion
As iMCD is rare, knowledge of its clinical and prognostic features has slowly accumulated. Our retrospective study in a large cohort confirmed the particularities of iMCD-IPL and demonstrated that iMCD-IPL had unique clinical manifestations, treatment responses, and prognoses compared with the other iMCD-NOS subtypes.
Compared with the iMCD-NOS w/o IPL group, laboratory examinations revealed significantly higher inflammatory syndrome in the iMCD-IPL group. These findings were strongly consistent with those of previous reports, although with slight differences in the definitions of IPL (Mori et al., Koijima et al., and Zhang et al., Supplementary Table S1). The first two sets of criteria do not specify platelet levels; nevertheless, thrombocytosis was indeed more commonly observed in the IPL group under previous criteria (9, 11). In addition, these criteria have stringent requirements for serum IgG levels. In our study, nearly one-third of patients with iMCD-IPL (n=30) did not meet Kojima et al.’s definition, mainly because they did not meet the polyclonal hypergammaglobulinaemia criteria. In 1980, Mori et al. found 10 cases with distinct clinical and histopathological features (6) and first defined the criteria for hypergammaglobulinaemia in IPL as a serum IgG level of >45 g/L. In 2009, Kojima et al. (11) identified 18 patients with IPL, modified the criteria and lowered the bar for hypergammaglobulinaemia to serum IgG >35 g/L. We adopted the criteria of Zhang et al. from 97 patients with iMCD-IPL and set the cut-off value as serum IgG >17.4 g/L according to the reference interval standard in China (12). To further identify patients in the ‘grey area’ between the different sets of criteria, subgroup analyses of baseline characteristics and survival were performed for patients with iMCD-IPL who did not meet the definition of Kojima et al. and those who did. There were no significant differences in the levels of haemoglobin, serum creatinine, CRP, and IL-6 between the two groups. However, these results significantly differed between the iMCD-IPL-not meeting the definition of Kojima et al. and iMCD-NOS groups (Supplementary Table S2). Survival analysis revealed no significant differences between the two iMCD-IPL subgroups (Supplementary Figure S1). The results suggest the plausibility of Zhang et al.’s criteria and that these highly similar disease entities may eventually point to a uniform population. Notably, the threshold of gamma globulin levels remains an unsolved issue not only in the diagnosis of iMCD-IPL, but also in that of TAFRO syndrome(13).
In this study, compared with lymphoma-like treatment strategy, patients with iMCD-IPL benefitted more from a multiple myeloma-like and IL-6 blocking treatment strategy, which was associated with a higher response rate and, importantly, a longer median TTNT. Thalidomide was the most commonly used treatment regimen in both groups. Although more non-first-line use was observed in iMCD-IPL, thalidomide showed significantly better response rates in iMCD-IPL than in iMCD-NOS without IPL. Thalidomide has direct inhibitory effects on plasma cells and inhibits the production of certain cytokines that are significantly elevated during disease flares (14). Our previous phase 2 study showed a significant decrease in IL-6 levels in patients who responded to thalidomide-based treatment (15). However, this study did not provide sufficient evidence for the efficacy of IL-6 targeted therapy for patients with iMCD-IPL, as siltuximab was not available on the Chinese market until 2022 and tocilizumab was expensive and not approved for iMCD in China.
IL-6 stimulates the maturation of B cells and megakaryocytes, increases plasma cell production of immunoglobulin, and causes thrombocytosis (16–19). Although IL-6 levels are not highly elevated in all patients with iMCD (4, 20, 21), our results showed a significant increase in IL-6 levels in patients with iMCD-IPL, accompanied by plasmacytic-dominant histopathology, thrombocytosis, hypergammaglobulinaemia, and proinflammatory hypercytokinaemia, suggesting that IL-6 may be a disease driver in this group of patients. Morra et al. (22) performed a secondary analysis based on the results of a phase II trial by van Rhee et al. (23) to identify the predictors of siltuximab response. They found that the responders showed less vascularised lymph node histopathology, higher CRP and IgG levels, and lower albumin and haemoglobin levels at baseline. These results are further supported by a proteome analysis of patients with iMCD showing that siltuximab responders fall into a distinct cluster with significantly higher disease activity scores (24). These findings raise the question of whether iMCD-IPL is the best candidate for IL-6 targeted therapy. In addition, Pierson et al. (24) reported that proteomic heterogeneity in patients with iMCD was greater than any signal of response biomarkers, suggesting a need to further subclassify iMCD to help improve outcomes.
In 1980, Mori et al. initially profiled 10 cases of iMCD-IPL with an indolent disease course for years (6). The inert course of iMCD-IPL was further confirmed in a 20-year data review of 40 centres by Zhang et al. (5). Our study showed significantly better OS in iMCD-IPL compared with iMCD-NOS w/o IPL. Although Kojima et al. reported no difference in the 5-year OS rate between the IPL and non-IPL subtypes, we hypothesise that this inconsistency may be mainly due to small sample sizes (11). In 2018, the CDCN consensus treatment guidelines proposed the concept of severe iMCD as a subgroup of patients with an increased risk of death. However, this criterion may not be applicable to patients with iMCD-IPL as no difference in OS between severity classes was observed (10). As the iMCD-IPL group occupies up to 45.2% of the iMCD-NOS spectrum and is unsuitable for iMCD-NOS risk stratification, understanding iMCD-IPL may also help modify risk stratification.
Our study has some limitations. First, owing to the retrospective nature of this study, the observed differences in TTNT between the multiple myeloma-like and IL-6 blocking treatments and lymphoma-like treatment strategies could be an artefact of the treatment duration. Second, iMCD-IPL appeared to be more sensitive to IL-6 targeted therapy. The limited access to IL-6 targeted therapy in China might result in the favourable therapeutic responsiveness of iMCD-IPL being underestimated. Identifying patients most likely to benefit from this therapy is paramount and our future studies aim to collect the relevant data, given that siltuximab is now available in China. Third, our centre is the national referral centre for rare diseases and accepts patients nationwide. Patients with iMCD-IPL have a relatively mild clinical presentation and better prognosis; thus, they are more likely to present at our outpatient clinic and be enrolled in this study, resulting in a relatively higher proportion of iMCD-IPL in our cohort.
In conclusion, these findings suggest that iMCD-IPL should be separated from the existing classification system and considered a distinct entity within the larger category of iMCD.
Supplementary Material
Funding
This work was supported by the CAMS Innovation Fund for Medical Sciences [Grant 2021-1-I2M-019 to J. L.], the Dongcheng District Outstanding Talent Nurturing Program [Grant 2022-dchrcpyzz-69 to L. Z.], the National High Level Hospital Clinical Research Funding [Grant 2022-PUMCH-A-021 to L. Z.], and the Research and Translation Application of Beijing Clinical Diagnostic Technologies Funds from Beijing Municipal Commission of Science and Technology [Grant Z211100002921016 to L. Z.].
Footnotes
Conflict of interest
D.C.F has received research funding from NHLBI and FDA and research funding and consulting fees from EUSA Pharma. The remaining authors declare no competing financial interests.
Data availability statement
The data that support the findings of this study are available from the corresponding author (J.L.) upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the corresponding author (J.L.) upon reasonable request.